Highly stable pyrylium derivatives with photoprotective and whitening activity, and preparation method and application thereof

Abstract

The present application relates to a kind of high-stable pyrylium alcohol derivatives with light protection, whitening activity and its preparation method and application.The present application is based on the molecular structure of pyrylium alcohol and is connected with different cinnamic acid side chain, obtains a series of cinnamic acid side chain modified pyrylium alcohol derivatives.The pyrylium alcohol derivatives of the present application can effectively improve the chemical stability of pyrylium alcohol, effectively solve the discoloration and inactivation problem of pyrylium alcohol in cosmetic formula.The pyrylium alcohol derivatives of the present application have excellent chemical stability, have the ability of rapid oxidation resistance, and can realize precise synergistic effect at cell level, the activity of inhibiting melanin, antioxidant and light protection in organism is significantly better than pyrylium alcohol.The pyrylium alcohol derivatives of the present application have higher fat solubility and lower effective concentration, can be used for preparing whitening, antioxidant, light protection and other cosmetics, and have important market value.

Description

Highly stable pyranol derivatives with photoprotective and whitening activities, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of cosmetics and pharmaceutical technology, and relates to active compounds with whitening, antioxidant and photoprotective properties. Specifically, it relates to a highly stable pyranol derivative with photoprotective and whitening activities, its preparation method and application. Background Technology

[0002] Dimethylmethoxybenzodihydropyranol is a tocopherol-like compound prepared by means of biological antioxidants. It has significant antioxidant activity and can reduce the synthesis of melanin in cells by inhibiting the activity of cellular tyrosinase. In addition, it can effectively reduce the damage to cells caused by ultraviolet radiation. It has great application prospects in whitening, repairing, anti-oxidation and photoprotection products in the cosmetics industry.

[0003] The core structure of pyranol is benzodihydropyran, with its 6-position phenolic hydroxyl group being a key site for antioxidant activity. However, the presence of this phenolic hydroxyl group also leads to poor stability and high irritation in pyranol. Under conditions such as oxygen and light, the phenolic hydroxyl group loses a hydrogen atom to generate a phenoxy radical, which is further oxidized to quinone compounds, causing yellowing and loss of efficacy. Furthermore, the irritation caused by this structure limits its addition in formulations, typically requiring a concentration below 0.1%. Therefore, pyranol is currently mainly used in cosmetics as a co-antioxidant to prevent the oxidation and rancidity of oils, and its use as a high-concentration active ingredient is difficult to promote, severely restricting its application potential.

[0004] Esterification modification can effectively improve the chemical stability of pyranol by blocking the oxidation of phenolic hydroxyl groups. Chinese invention patent CN101730689A discloses a pyranol derivative that can effectively improve the stability and decolorizing efficacy of pyranol. However, according to its experimental data, the effective concentration of its preferred derivative is relatively high; in in vitro cell experiments, the melanin inhibition rate at a concentration of 100 μM is 45.9%, which is relatively weaker compared to domestic whitening active ingredients such as glycyrrhizin and 577 (effective concentrations of approximately 5 μM to 20 μM).

[0005] Therefore, developing novel pyranol derivatives with better stability and lower effective concentrations has significant research value and application implications. Summary of the Invention

[0006] Based on this, the purpose of this invention is to provide a pyranol derivative with good stability and low effective concentration that has photoprotective and whitening activities.

[0007] The technical solutions for achieving the above objectives include the following.

[0008] In a first aspect, the present invention provides a pyranol derivative having the structure shown in formula (I) or its cis-trans isomer,

[0009]

[0010] (I)

[0011] Among them, R1, R2, R3, R4, and R5 are independently selected from: hydrogen, C1-C6 alkoxy, and chlorine, respectively;

[0012] At least one of R2, R3, and R4 is hydrogen, and at least one of R1, R3, and R5 is hydrogen.

[0013] Secondly, the present invention provides a method for preparing the pyranol derivative or its cis-trans isomer, comprising the following steps:

[0014] A cinnamic acid derivative having the structure shown in formula (II) or its cis-trans isomer is esterified with dimethylmethoxybenzodihydropyranol to obtain the pyranol derivative having the structure shown in formula (I) or its cis-trans isomer.

[0015]

[0016] II

[0017] Among them, R1, R2, R3, R4, and R5 are independently selected from: hydrogen, C1-C6 alkoxy, and chlorine, respectively;

[0018] At least one of R2, R3, and R4 is hydrogen, and at least one of R1, R3, and R5 is hydrogen.

[0019] Thirdly, the present invention provides the use of the pyranol derivatives or their cis-trans isomers in the preparation of cosmetics or topical skin medications with whitening, antioxidant and / or photoprotective effects.

[0020] Fourthly, the present invention provides a cosmetic or topical skin medicine, the active ingredient of which includes the pyranol derivative or its cis-trans isomer described in the present invention.

[0021] The present invention has the following beneficial effects:

[0022] This invention involves incorporating different cinnamic acid side chains into the pyranol molecular structure to obtain a series of cinnamic acid-modified pyranol derivatives. These pyranol derivatives effectively improve the chemical stability of pyranol, effectively solving the problems of discoloration and inactivation of pyranol in cosmetic formulations. While possessing excellent chemical stability, these pyranol derivatives also exhibit rapid antioxidant capabilities and achieve precise synergistic effects at the cellular level. Their activities in inhibiting melanin, anti-oxidation, and photoprotection in vivo are significantly superior to those of pyranol. Furthermore, these pyranol derivatives have a low effective concentration and high lipid solubility, making them suitable for preparing whitening, antioxidant, and photoprotective cosmetics, thus possessing significant market value. Detailed Implementation

[0023] To facilitate understanding of the present invention, a more complete description will be provided below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0024] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. All commonly used chemical reagents used in the examples are commercially available products.

[0025] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used in this invention includes any and all combinations of one or more of the associated listed items.

[0026] Furthermore, as used herein, the term "or" is an inclusive "or" sign and is equivalent to the term "and / or" unless the context clearly specifies otherwise. The term "based on" is not exclusive and allows for basing on other factors not described unless the context clearly specifies otherwise. Additionally, throughout the specification, the meanings of "an," "a," and "the" include plural indicators. The meaning of "in" includes both "in" and "on."

[0027] In some embodiments of the present invention, a pyranol derivative having the structure shown in formula (I) or its cis-trans isomer is involved.

[0028]

[0029] (I)

[0030] Among them, R1, R2, R3, R4, and R5 are independently selected from: hydrogen, C1-C6 alkoxy, and chlorine, respectively;

[0031] At least one of R2, R3, and R4 is hydrogen, and at least one of R1, R3, and R5 is hydrogen.

[0032] In some embodiments, R1, R2, R3, R4, and R5 are each independently selected from: hydrogen, methoxy, ethoxy, propoxy, and chlorine.

[0033] In some of these embodiments, R2, R3, and R5 are all hydrogen, while R1 and R4 are not hydrogen.

[0034] In some embodiments, R3, R4, and R5 are all hydrogen, while R1 and R2 are not hydrogen.

[0035] In some of these embodiments, R2, R4, and R5 are all hydrogen, while R1 and R3 are not hydrogen.

[0036] In some embodiments, R4 and R5 are both hydrogen, while R1, R2, and R3 are not hydrogen.

[0037] In some embodiments, R2, R3, and R5 are all hydrogen, and R1 and R4 are independently selected from methoxy and ethoxy, respectively.

[0038] In some embodiments, R3, R4, and R5 are all hydrogen, and R1 and R2 are independently selected from methoxy and ethoxy, respectively.

[0039] In some embodiments, R2, R4, and R5 are all hydrogen, and R1 and R3 are independently selected from methoxy and ethoxy, respectively.

[0040] In some embodiments, R4 and R5 are both hydrogen, and R1, R2 and R3 are independently selected from methoxy and ethoxy groups, respectively.

[0041] In some embodiments, the pyranol derivative is selected from the following compounds:

[0042]

[0043]

[0044] .

[0045] The pyranol derivatives of the present invention can be obtained by conventional esterification reaction of the corresponding cinnamic acid derivatives with dimethylmethoxybenzodihydropyranol.

[0046] For example, some embodiments of the present invention relate to a method for preparing the pyranol derivative or its cis-trans isomer described in the present invention, comprising the following steps:

[0047] A cinnamic acid derivative having the structure shown in formula (II) or its cis-trans isomer is esterified with dimethylmethoxybenzodihydropyranol to obtain the pyranol derivative having the structure shown in formula (I) or its cis-trans isomer.

[0048]

[0049] II

[0050] Among them, R1, R2, R3, R4, and R5 are independently selected from: hydrogen, C1-C6 alkoxy, and chlorine, respectively;

[0051] At least one of R2, R3, and R4 is hydrogen, and at least one of R1, R3, and R5 is hydrogen.

[0052] In some embodiments, the esterification reaction is carried out in the presence of a catalyst and a condensing agent. The catalyst is selected from one or more of 4-dimethylaminopyridine, 1-hydroxybenzotriazole, 6-chloro-1-hydroxybenzotriazole, N-hydroxy-7-azabenzotriazole, ethyl 2-oxime cyanoacetate, and 1,3-dimethyl-2,4,5,6(1H,3H)-pyrimidinide-5-oxime. The condensing agent is selected from 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, benzotriazole-N,N,N', One or more of the following: N'-tetramethylurea hexafluorophosphate, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate, benzotriazole-1-oxytris(dimethylamino)phosphide hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinephosphide hexafluorophosphate, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride, diisopropylcarbodiimide, and dicyclohexylcarbodiimide.

[0053] In some embodiments, the molar ratio of the cinnamic acid derivative to dimethylmethoxybenzodihydropyranol is 1:0.8-1.2.

[0054] In some embodiments, the solvent for the esterification reaction is one or more of dichloromethane, toluene, xylene, chlorobenzene, dichlorobenzene, dichloroethane, methyl tert-butyl ether, methyl cyclopentyl ether, isopropyl ether, dibutyl ether, isopropyl acetate, ethyl butyl ester, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, and N-butylpyrrolidone.

[0055] In some embodiments, the esterification reaction is carried out at a temperature of 15°C-35°C for 3-8 hours.

[0056] In some embodiments, the molar ratio of the cinnamic acid derivative to the catalyst is 1:0.03-0.08.

[0057] In some embodiments, the molar ratio of the cinnamic acid derivative to the condensing agent is 1:1.5-2.5.

[0058] This invention involves incorporating different cinnamic acid side chains into the pyranol molecule to obtain a series of cinnamic acid-modified pyranol derivatives. Previous research revealed that cinnamic acid with different structures exhibits varying synergistic effects with pyranol. The optimized pyranol derivatives of this invention achieve precise synergistic effects at the cellular level, significantly enhancing their melanin-inhibiting, antioxidant, and photoprotective activities compared to pyranol. Furthermore, they possess better chemical stability, higher lipid solubility, and a lower effective concentration, making them suitable for use in the preparation of cosmetics with whitening, antioxidant, and photoprotective properties.

[0059] Some embodiments of the present invention relate to the use of the pyranol derivatives or their cis-trans isomers in the preparation of cosmetics or topical skin medications with whitening, antioxidant and / or photoprotective effects.

[0060] Some embodiments of the present invention relate to a cosmetic or topical skin medicine whose active ingredient includes the pyranol derivative or its cis-trans isomer described in the present invention.

[0061] The present invention will be further described in detail below with reference to specific embodiments.

[0062] Example 1: Preparation of 3,4-(methylenedioxy)cinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-001)

[0063]

[0064] 3,4-(methylenedioxy)cinnamic acid (19.2 g, 0.1 mol), dimethylmethoxybenzodihydropyranol (20.8 g, 0.1 mol), and 4-dimethylaminopyridine (0.61 g, 5 mmol) were dissolved in dichloromethane (500 mL). 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 38.4 g, 0.2 mol) was added at room temperature and reacted for 5 hours. Purified water (500 mL) was added, and the mixture was stirred for 5 minutes. The aqueous layer was separated, and the organic layer was washed successively with 1N hydrochloric acid (200 mL), purified water (200 mL), and saturated brine (200 mL). The mixture was concentrated to obtain a crude product. 200 mL of anhydrous ethanol was added, and the mixture was stirred for half an hour. The product was filtered to obtain 37.5 g of 3,4-(methylenedioxy)cinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-001), with a yield of 98.1%.

[0065] 1 H-NMR (500MHz, CDCl3): δ7.71-7.64 (d,1H), 7.12-7.05 (m,2H), 6.96-6.92 (s,1H), 6.87-6.82 (d,1H), 6.61-6.57 (s,1H), 6.51- 6.44 (d,1H), 6.02-5.99 (s,2H), 3.85-3.81 (s,3H), 2.85-2.79 (m,1H), 2.78-2.71 (m,1H), 2.03-1.96 (m,2H), 1.34-1.31 (s,6H). MS(ESI):383.14[M+H] + .

[0066] Example 2 Preparation of 4-methoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-002)

[0067]

[0068] The procedure was the same as in Example 1, except that 4-methoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 4-methoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-002), with a yield of 98.5%.

[0069] 1H-NMR (500MHz, CDCl3): δ7.64-7.56 (m, 3H), 6.95-6.89 (m, 3H), 6.63-6.60 (m, 1H), 6.48-6.41 (m, 3 H), 3.84-3.80 (m, 6H), 2.85-2.79 (m, 1H), 2.78-2.71 (m, 1H), 2.03-1.96 (m, 2H), 1.34-1.31 (s, 6H). MS(ESI):369.12[M+H] + .

[0070] Example 3 Preparation of 2-methoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-003)

[0071]

[0072] The procedure was the same as in Example 1, except that 2-methoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2-methoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-003), with a yield of 92.0%.

[0073] 1 H-NMR (500MHz, CDCl3): δ7.82-7.75 (d, 1H), 7.62-7.57 (m, 1H), 7.39-7.32 (m, 1H), 7.05-6.98 (m, 1H), 6.96-6.90 (m, 2H), 6.63-6.60 (s, 1 H), 6.47-6.40 (d, 1H), 3.90-3.86 (s, 3H), 3.84-3.81 (s, 3H), 2.85-2.79 (m, 1H), 2.78-2.71 (m, 1H), 2.03-1.96 (t, 2H), 1.34-1.31 (s, 6H). MS(ESI):369.16[M+H] + .

[0074] Example 4 Preparation of 2,5-dimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-004)

[0075]

[0076] The procedure was the same as in Example 1, except that 2,5-dimethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2,5-dimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-004), with a yield of 97.5%.

[0077] 1H-NMR (500MHz, CDCl3): δ7.86-7.80 (d, 1H), 7.27-7.23 (d, 1H), 6.96-6.9 2 (m, 1H), 6.92-6.87 (s, 1H), 6.85-6.79 (s, 1H), 6.62-6.59 (m, 1H), 6.47- 6.41 (m, 1H), 3.90-3.86 (s, 3H), 3.85-3.81 (s, 3H), 3.81-3.77 (s, 3H), 2. 85-2.79 (m, 1H), 2.78-2.71 (m, 1H), 2.03-1.96 (t, 2H), 1.34-1.31 (s, 6H). MS (ESI): 399.10 [M+H] + .

[0078] Example 5 Preparation of 3,4,5-trimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-005)

[0079]

[0080] The procedure was the same as in Example 1, except that 3,4,5-trimethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 3,4,5-trimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-005), with a yield of 95.5%.

[0081] 1 H-NMR (500MHz, CDCl3): δ7.71-7.64 (d,1H), 6.97-6.93 (m,1H), 6.93-6.89(s,2H), 6.62-6.59 (s,1H), 6.53-6.46 (d,1H), 3.88-3.83 (m,9H), 3.81-3.78 (s,3H), 2.88-2.81 (m,1H), 2.78-2.71 (m,1H), 2.03-1.96 (t,2H), 1.34-1.31 (s,6H). MS(ESI):428.18[M+H] + .

[0082] Example 6 Preparation of 3,4-dimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-006)

[0083]

[0084] The procedure was the same as in Example 1, except that 3,4-dimethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 3,4-dimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-006), with a yield of 96.0%.

[0085] 1 H-NMR (500MHz, CDCl3): δ7.72-7.65 (d,1H), 7.20-7.12 (m,2H), 6.96-6.92(s,1H), 6.90-6.85 (d,1H), 6.62-6.59 (s,1H), 6.51-6.44 (d,1H), 3.88-3.81 (m,9H), 2.85-2.79 (s,1H), 2.78-2.71 (m,1H), 2.03-1.96 (t,2H), 1.34-1.31 (s,6H). MS(ESI):399.10[M+H] + .

[0086] Example 7 Preparation of 2-methoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-007)

[0087]

[0088] The procedure was the same as in Example 1, but 2-methoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2-methoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-007), with a yield of 97.0%.

[0089] 1 H-NMR (500MHz, CDCl3): δ7.29-7.22 (m,1H), 7.18-7.12 (m,1H), 7.00-6.94(m,1H), 6.94-6.90 (m,1H), 6.87-6.82 (m,1H), 6.66-6.62 (s,1H), 3.87-3.81 (m,6H), 2.93-2.87 (m,2H), 2.86-2.79 (m,3H), 2.78-2.71 (m, 1H), 2.03-1.96 (t, 2H), 1.34-1.31 (s, 6H). MS(ESI):371.18[M+H] + .

[0090] Example 8 Preparation of 2,3-dimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-008)

[0091]

[0092] The procedure was the same as in Example 1, except that 2,3-dimethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2,3-dimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-008), with a yield of 98.0%.

[0093] 1 H-NMR (500MHz, CDCl3): δ7.86-7.80 (d,1H), 7.20-7.15 (m,1H), 7.14-7.08(m,1H), 6.96-6.91 (m,2H), 6.62-6.59 (s,1H), 6.47-6.41 (d,1H), 3.88-3.81 (m,9H), 2.85-2.79 (m,1H), 2.78-2.71 (m, 1H), 2.03-1.96 (t, 2H), 1.34-1.31 (s, 6H). MS(ESI):399.16[M+H] + .

[0094] Example 9 Preparation of 2,4-dimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-009)

[0095]

[0096] The procedure was the same as in Example 1, except that 2,4-dimethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2,4-dimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-009), with a yield of 98.5%.

[0097] 1 H-NMR (500MHz, CDCl3): δ8.12-8.07 (d,1H), 7.85-7.79 (d,1H), 6.96-6.92(s,1H), 6.80-6.77 (m,1H), 6.77-6.72 (m,1H), 6.62-6.59 (s,1H), 6.47-6.40 (d,1H), 3.86-3.81 (m,9H), 2.85-2.79 (m,1H), 2.78-2.71 (m, 1H), 2.03-1.96 (t, 2H), 1.34-1.31 (s, 6H). MS(ESI):399.14[M+H] + .

[0098] Example 10 Preparation of 2,6-dimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-010)

[0099]

[0100] The procedure was the same as in Example 1, but 2,6-dimethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2,6-dimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-010), with a yield of 94.5%.

[0101] 1 H-NMR (500MHz, CDCl3): δ7.92-7.85 (d,1H), 7.28-7.22 (t,1H), 6.96-6.92(t,1H), 6.74-6.69 (d,2H), 6.62-6.59 (s,1H), 6.47-6.40 (d,1H), 3.85-3.81 (m,9H), 2.85-2.79 (m,1H), 2.78-2.71 (m, 1H), 2.03-1.96 (t, 2H), 1.34-1.31 (s, 6H). MS(ESI):399.20[M+H] + .

[0102] Example 11 Preparation of Z-2-methoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-011)

[0103]

[0104] The procedure was the same as in Example 1, except that Z-2-methoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize Z-2-methoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-011), with a yield of 94.0%.

[0105] 1H-NMR (500MHz, CDCl3): δ7.66-7.57 (m,2H), 7.39-7.32 (m,1H), 7.07-7.00(m,1H), 6.96-6.90 (m,2H), 6.63-6.60 (s,1H), 6.36-6.30 (d,1H), 3.90-3.86 (s,3H), 3.84-3.81 (s,3H), 2.85-2.79 (m,1H), 2.78-2.71 (m,1H), 2.03-1.96 (t,2H), 1.34-1.31 (s,6H). MS(ESI):369.14[M+H] + .

[0106] Example 12 Preparation of 2,3,4-trimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-012)

[0107]

[0108] The procedure was the same as in Example 1, except that 2,3,4-trimethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2,3,4-trimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-012), with a yield of 97.0%.

[0109] 1 H-NMR (500MHz, CDCl3): δ7.88-7.81 (d,1H), 7.78-7.73 (d,1H), 6.98-6.93(m,2H), 6.62-6.59 (s,1H), 6.48-6.42 (d,1H), 3.90-3.83 (m,12H), 2.85-2.79 (m,1H), 2.78-2.71 (m,1H), 2.03-1.96 (t,2H), 1.34-1.31 (s,6H). MS(ESI):429.19[M+H] + .

[0110] Example 13 Preparation of 2,4,5-trimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-013)

[0111]

[0112] The procedure was the same as in Example 1, except that 2,4,5-trimethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2,4,5-trimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-013), with a yield of 96.5%.

[0113] 1 H-NMR (500MHz, CDCl3): δ7.88-7.81 (d,1H), 7.63-7.59 (s,1H), 6.97-6.93(m,1H), 6.89-6.85 (s,1H), 6.62-6.59 (s,1H), 6.48-6.42 (d,1H), 3.89-3.83 (m,12H), 2.85-2.79 (m,1H), 2.78-2.71 (m, 1H), 2.03-1.96 (t, 2H), 1.34-1.31 (s, 6H). MS(ESI):429.12[M+H] + .

[0114] Example 14 Preparation of 2,5,6-trimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-014)

[0115]

[0116] The procedure was the same as in Example 1, except that 2,5,6-trimethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2,5,6-trimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-014), with a yield of 95.5%.

[0117] 1 H-NMR (500MHz, CDCl3): δ7.90-7.83 (d,1H), 6.97-6.93 (m,1H), 6.76-6.68(m,2H), 6.62-6.59 (s,1H), 6.49-6.42 (d,1H), 3.89-3.83 (m,12H), 2.85-2.79 (m,1H), 2.78-2.71 (m,1H), 2.03-1.96 (t,2H), 1.34-1.31 (s,6H). MS(ESI):429.16[M+H] + .

[0118] Example 15 Preparation of 2-ethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-015)

[0119]

[0120] The procedure was the same as in Example 1, except that 2-ethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2-ethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-015), with a yield of 98.5%.

[0121] 1 H-NMR (500MHz, CDCl3): δ7.82-7.75 (d,1H), 7.60-7.55 (m,1H), 7.37-7.30(m,1H), 7.05-6.99 (m,1H), 6.96-6.91 (m,2H), 6.61-6.57 (s,1H), 6.47-6.40 (d,1H), 4.18-4.09 (m,2H), 3.85-3.81 (s,3H),2.85-2.79 (m,1H), 2.78-2.71 (m,1H), 2.03-1.96 (t,2H), 1.50-1.44 (t,3H), 1.34-1.31 (s, 6H). MS(ESI): 383.18 [M+H] + .

[0122] Example 16 Preparation of 2-chlorocinnamate dimethylmethoxybenzodihydropyranol ester (CG-CHR-016)

[0123]

[0124] The procedure was the same as in Example 1, but 2-chlorocinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2-chlorocinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-016), with a yield of 99.0%.

[0125] 1 H-NMR (500MHz, CDCl3): δ7.77-7.70 (d,1H), 7.56-7.51 (m,1H), 7.45-7.34(m,3H), 6.95-6.91 (sm,1H), 6.63-6.60 (s,1H), 6.46-6.39 (d,1H), 3.85-3.81 (s,3H), 2.80-2.73 (m,2H), 2.03-1.96 (t, 2H), 1.34-1.31 (s, 6H). MS(ESI):373.12[M+H] + .

[0126] Example 17 Preparation of 2-Fluorocinol dimethylmethoxybenzodihydropyranol ester (CG-CHR-017)

[0127]

[0128] The procedure was the same as in Example 1, but 2-fluorocinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2-fluorocinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-017), with a yield of 98.5%.

[0129] 1 H-NMR (500MHz, CDCl3): δ7.90-7.83 (d,1H), 7.63-7.57 (m,1H), 7.49-7.41(m,1H), 7.29-7.22 (m,1H), 7.16-7.09 (m,1H), 6.95-6.91 (m,1H), 6.63-6.60 (s,1H), 6.54-6.47 (d,1H), 3.86-3.82 (s,3H), 2.80-2.73 (m,2H), 2.03-1.96 (t, 2H), 1.34-1.31 (s, 6H). MS(ESI):357.15[M+H] + .

[0130] Example 18 Preparation of dimethyl methoxybenzodihydropyranol cinnamate (CG-CHR-018)

[0131]

[0132] The procedure was the same as in Example 1, but cinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize dimethyl methoxybenzodihydropyranol ester of cinnamic acid (CG-CHR-018), with a yield of 98.0%.

[0133] 1 H-NMR (500MHz, CDCl3): δ7.84-7.77 (d,1H), 7.60-7.54 (m,2H), 7.42-7.39(m,1H), 7.39-7.30 (m,2H), 6.96-6.92 (s,1H), 6.62-6.59 (s,1H), 6.48-6.42 (d,1H), 3.84-3.80 (s,3H), 2.80-2.73 (m,2H), 2.03-1.96 (t, 2H), 1.34-1.31 (s, 6H). MS(ESI):339.16[M+H] + .

[0134] Example 19 Preparation of 2,4,6-trimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-019)

[0135]

[0136] The procedure was the same as in Example 1, but 2,4,6-trimethoxycinnamic acid was used instead of 3,4-(methylenedioxy)cinnamic acid to synthesize 2,4,6-trimethoxycinnamic acid dimethylmethoxybenzodihydropyranol ester (CG-CHR-019), with a yield of 96.5%.

[0137] 1 H-NMR (500MHz, CDCl3): δ7.93-7.86 (d,1H), 6.97-6.93 (m,1H), 6.62-6.59(s,1H), 6.50-6.40 (m,3H), 3.92-3.88 (s,6H), 3.88-3.83 (ss,6H), 2.88-2.81 (m,1H), 2.78-2.72 (m,1H), 2.03-1.96 (t,2H), 1.34-1.31 (s,6H). MS(ESI):429.15[M+H] + .

[0138] Comparative Example 1

[0139] Commercially available 7-methoxy-6-palmitoyl-2,2-dimethylchromane (pyran whitening agent), purity ≥98%.

[0140] Comparative Example 2

[0141] Commercially available phenylethyl resorcinol (377), purity ≥98%.

[0142] Comparative Example 3

[0143] Commercially available 4-butylresorcinol (577), purity ≥98%.

[0144] Comparative Example 4

[0145] A mixture of 2,5-di-methoxycinnamic acid and dimethylmethoxybenzodihydropyranol in a molar ratio of 1:1 (i.e., the reaction raw materials of Example 4).

[0146] Comparative Example 5

[0147] A mixture of 2,3-dimethoxycinnamic acid and dimethylmethoxybenzodihydropyranol in a molar ratio of 1:1 (i.e., the reaction raw materials of Example 8).

[0148] Comparative Example 6

[0149] A mixture of 2,3,4-trimethoxycinnamic acid and dimethylmethoxybenzodihydropyranol in a molar ratio of 1:1 (i.e., the reaction raw materials of Example 12).

[0150] Comparative Example 7

[0151] Commercially available dimethylmethoxybenzodihydropyranol with a purity ≥98%.

[0152] Test Example 1: Chemical Stability Test

[0153] Prepare a cream containing active ingredients according to the formula in Table 1. The preparation method is as follows:

[0154] Phase A and Phase B are heated and stirred at 80℃-85℃ respectively until they are evenly dispersed. Phase B is then added to Phase A and kept at 80℃-85℃. The mixture is homogenized at 9000r / min for 3-5 minutes. After cooling to 45℃, Phase C is added and stirred until evenly dispersed. Then, the evenly dispersed Phase D and Phase E are added and stirred until completely dispersed to obtain a cream with an active ingredient concentration of 0.1%.

[0155] The active substances to be tested in Table 1 are the pyranol derivatives prepared in Examples 1-19, phenylethyl resorcinol and 4-butyl resorcinol in Comparative Examples 2-3, and dimethyl methoxybenzodihydropyranol in Comparative Example 7.

[0156] The obtained creams were stored at 40±2℃ and 40±2℃ under light conditions (illuminance of 4500IX±500IX), respectively. The appearance of the creams was recorded and the content of pyranol derivatives (or phenylethyl resorcinol, 4-butyl resorcinol and dimethyl methoxybenzodihydropyranol) was detected at 0 days, 15 days, 30 days and 60 days. The test results are shown in Table 2.

[0157] Table 1. Cream Formulas

[0158]

[0159]

[0160] Table 2. Stability test results for each group under different conditions (content (%) / appearance)

[0161]

[0162]

[0163]

[0164] Table 2 shows that after 15 days of storage under light conditions at 40±2℃, Comparative Examples 2, 3, and 7 exhibited significant color changes, transforming from a white paste to a light red / orange-red / light yellow paste. The content of Comparative Example 3 decreased to 0.083%. Upon continued storage under these conditions for 30 days, the contents of Comparative Examples 2, 3, and 7 decreased to 0.090%, 0.065%, and 0.088%, respectively. This result indicates that the whitening ingredients such as 377 and 577 have extremely poor photostability. Under the same storage conditions, the appearance and content of the pyranol derivative cream prepared in this invention showed no significant changes. This demonstrates that the pyranol derivative prepared in this invention possesses excellent photochemical stability, solving the problem of traditional whitening agents being extremely sensitive to light and high temperatures during production and storage.

[0165] Test Example 2: DPPH Free Radical Scavenging Capacity Test

[0166] Weigh 3.9 mg of DPPH, dissolve it in an appropriate amount of anhydrous ethanol, sonicate it in the dark until fully dissolved, and bring the volume to 100 mL with anhydrous ethanol to prepare a DPPH working solution with a concentration of 0.1 mmol / L. Prepare a 40 mM test solution by mixing the pyranol derivatives prepared in each example with the pyran whitening agent of Comparative Example 1, using a DMSO solution containing 20% ​​hydroxypropyl-β-cyclodextrin as the solvent. In a 96-well plate, add 50 μl of the test solution to the sample group, 50 μl of the solvent to the blank group, and then add 200 μl of DPPH working solution to each well. Set up a background group (replace the DPPH working solution with an equal amount of ethanol). Mix well and react at room temperature in the dark for 30 min. Detect the absorbance of each group at a wavelength of 517 nm using an ELISA reader. Calculate the DPPH free radical scavenging rate according to formula (1) based on the absorbance. Set up 3 replicates for each concentration. The results are shown in Table 3.

[0167] DPPH free radical scavenging rate (%) = (1)

[0168] In the formula: C1—OD value of the blank group containing DPPH system

[0169] C2—OD value of the blank group without DPPH system

[0170] T1—OD value of the DPPH system in the sample group

[0171] T2—OD value of the DPPH-free system in the sample group

[0172] Table 3. Scavenging rates of DPPH free radicals by each group of compounds

[0173]

[0174]

[0175] Table 3 shows that different side chains have different effects on the activity of the compounds. Among them, the pyranol derivatives prepared in Examples 3, 4, 9, 12, 16, and 18 have a strong ability to scavenge DPPH free radicals, with scavenging rates all greater than 60%. In contrast, at the same concentration, the scavenging rate of the pyran whitening agent in Comparative Example 1 is only 18.23%. These results indicate that the pyranol derivatives prepared in this invention have excellent chemical stability and rapid antioxidant capacity, and the effect is significantly better than that of the pyran whitening agent.

[0176] Test Example 3: Test of the ability of B16F10 cells to inhibit melanin synthesis

[0177] B16F10 cells stored in liquid nitrogen were revived, stabilized in RPMI complete medium, and passaged twice. Then, they were cultured at 5 × 10⁻⁶ cells / year. 5 / wells were inoculated into 6-well plates, and the plates were incubated at 37°C in a 5% CO2 incubator for 24 h.

[0178] The pyranol derivatives prepared in each example were dissolved in DMSO solution containing 20% ​​hydroxypropyl-β-cyclodextrin to obtain sample stock solutions, along with the pyran whitening agent of Comparative Example 1, the dimethylmethoxybenzodihydropyranol of Comparative Example 7, and the mixtures of cinnamic acid and pyranol in Comparative Examples 4-6. DMEM complete medium containing 1 μM α-MSH was prepared, and the stock solutions were diluted to a concentration of 50 μM with medium containing α-MSH (for the mixtures of cinnamic acid and pyranol in Comparative Examples 4-6, the concentrations of pyranol and cinnamic acid were 50 μM each). 2 mL of the test solution was added to each well, and the plate was incubated at 37°C in a 5% CO2 incubator for 48 h. Cells were collected in 1.5 mL centrifuge tubes, centrifuged at 8000 rpm for 10 min, the supernatant was discarded, and 70 μL of 1 mol / L sodium hydroxide (containing 10% DMSO) aqueous solution was added to each tube. The tubes were then sonicated at 60°C for 30 min. The absorbance of each sample was measured at 417 nm using a microplate reader, and the relative melanin synthesis inhibition rate of each group was calculated. Three replicates were set up for each concentration. The results are shown in Table 4.

[0179] Relative melanin synthesis inhibition rate (%) = (2)

[0180] In formula (2):

[0181] V e —Melanin OD value of the sample group;

[0182] V c —Melanin OD value of the model group.

[0183] Table 4. Inhibition rate (%) of each compound on melanin synthesis

[0184]

[0185]

[0186] Since biochemical tests cannot reflect the permeability of active ingredients, cell experiments are needed to compare the melanin inhibition capabilities of each active ingredient in order to evaluate its overall activity after penetration. Table 4 shows that the compounds in most examples (except Examples 1, 5, 7, 17, and 19) showed better inhibitory effects on melanin synthesis than the pyran whitening agent in Comparative Example 1. Among them, the pyranol derivatives prepared in Examples 4, 8, 9, and 12 exhibited stronger inhibitory activity on melanin synthesis compared to the other examples.

[0187] Further comparative analysis of the pyranol derivatives prepared in Examples 4, 8, and 12 with the raw material mixtures of Comparative Examples 2-4 showed that the esterified derivative group exhibited significantly higher activity than the physically compounded group with its unesterified precursor. The pyranol derivatives obtained through chemical modification in this invention do not simply represent the sum of their precursor raw materials, but rather achieve a more precise cellular synergistic effect, thus demonstrating superior overall activity.

[0188] Test Example 4: HaCaT Cell Photoprotective Capacity Test

[0189] HaCaT cells preserved in liquid nitrogen were revived, stabilized in DMEM complete medium, and passaged twice. Then, they were cultured at 1×10⁻⁶ cells / year. 5 / wells were inoculated into 96-well plates, and the plates were incubated at 37°C in a 5% CO2 incubator for 24 h.

[0190] Sample stock solutions were prepared by dissolving the pyranol derivatives prepared in Examples 1-19, the pyran whitening agent in Comparative Example 1, and the mixtures of cinnamic acid and pyranol in Comparative Examples 4-6 in DMSO solution containing 20% ​​hydroxypropyl-β-cyclodextrin. The stock solutions were diluted with culture medium to a concentration of 20 μM for the test solution (for the mixtures of cinnamic acid and pyranol in Comparative Examples 4-6, the concentrations of pyranol and cinnamic acid were 20 μM each). 100 μL of test solution was added to each well of the sample group, and 100 μL of culture medium containing an equal mass concentration of solvent was added to each well of the blank and model groups. The plates were then incubated at 37°C in a 5% CO2 incubator for 24 h. After culture, the culture medium in the well plates was discarded, and the plates were washed twice with PBS. 50 μL of PBS was added to each well. The model group and sample group were irradiated in a UV aging chamber for 3 hours. The PBS was then discarded, and 100 μL of CCK8 working solution was added to each well. The plates were incubated at 37°C with 5% CO2 for 30 minutes. The absorbance of each sample was measured at 450 nm using a microplate reader, and the relative cell viability of each group was calculated. Three replicates were set up for each concentration. The results are shown in Table 5.

[0191] Relative cell viability (%) = (3)

[0192] In formula (3): Ve—OD value of sample group; Vc—OD value of blank control group.

[0193] Table 5. Relative cell survival rate (%) after ultraviolet irradiation in each group

[0194]

[0195]

[0196] As shown in Table 5, the pyranol derivatives prepared in each example all exhibited good protective effects on cells irradiated with ultraviolet light. Among them, the HaCaT cells treated with the pyranol derivatives prepared in Examples 4, 8, 9, and 12 showed significantly higher cell viability after ultraviolet light irradiation than the HaCaT cells treated with the pyran whitening agent in Comparative Example 1 and the mixture of cinnamic acid and pyranol in Comparative Examples 4-6.

[0197] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A pyranol derivative having the structure shown in formula (I) or its cis-trans isomer, (I) Among them, R1, R2, R3, R4, and R5 are each independently selected from: hydrogen, C1-C6 alkoxy, and chlorine; at least one of R2, R3, and R4 is hydrogen, and at least one of R1, R3, and R5 is hydrogen.

2. The pyranol derivative or its cis-trans isomer according to claim 1, characterized in that, R1, R2, R3, R4, and R5 are each independently selected from: hydrogen, methoxy, ethoxy, propoxy, and chlorine.

3. The pyranol derivative or its cis-trans isomer according to claim 1 or 2, characterized in that, R2, R3, and R5 are all hydrogen, while R1 and R4 are not hydrogen; or, R3, R4, and R5 are all hydrogen, while R1 and R2 are not hydrogen; or, R2, R4, and R5 are all hydrogen, while R1 and R3 are not hydrogen; or, R4 and R5 are all hydrogen, while R1, R2, and R3 are not hydrogen.

4. The pyranol derivative or its cis-trans isomer according to claim 3, characterized in that, R2, R3, and R5 are all hydrogen, and R1 and R4 are independently selected from: methoxy and ethoxy, respectively; or, R3, R4, and R5 are all hydrogen, and R1 and R2 are independently selected from: methoxy and ethoxy, respectively; or, R2, R4, and R5 are all hydrogen, and R1 and R3 are independently selected from: methoxy and ethoxy, respectively; or, R4 and R5 are all hydrogen, and R1, R2, and R3 are independently selected from: methoxy and ethoxy, respectively.

5. The pyranol derivative or its cis-trans isomer according to claim 1, characterized in that, The pyranol derivatives are selected from the following compounds: ； ； 。 6. A method for preparing a pyranol derivative or its cis-trans isomer according to any one of claims 1-5, characterized in that, The process includes the following steps: esterification of a cinnamic acid derivative having the structure shown in formula (II) or its cis-trans isomer with dimethylmethoxybenzodihydropyranol to obtain the pyranol derivative having the structure shown in formula (I) or its cis-trans isomer; II. Wherein, R1, R2, R3, R4, and R5 are as described in any one of claims 1-5.

7. The method for preparing pyranol derivatives or their cis-trans isomers according to claim 6, characterized in that, The esterification reaction is carried out in the presence of a catalyst and a condensing agent. The catalyst is selected from one or more of 4-dimethylaminopyridine, 1-hydroxybenzotriazole, 6-chloro-1-hydroxybenzotriazole, N-hydroxy-7-azabenzotriazole, ethyl 2-oxime cyanoacetate, and 1,3-dimethyl-2,4,5,6(1H,3H)-pyrimidinetetraone 5-oxime. The condensing agent is selected from 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate, benzotriazole-1-oxytris(dimethylamino)phosphide, and benzotriazole-1-oxotriazole hexafluorophosphate. One or more of the following: -yl-oxytripyrrolidinephosphine, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine, diisopropylcarbodiimide, and dicyclohexylcarbodiimide; or, the molar ratio of the cinnamic acid derivative or its cis-trans isomer to dimethylmethoxybenzodihydropyranol is 1:0.8-1.2; or, the solvent for the esterification reaction is one or more of the following: dichloromethane, toluene, xylene, chlorobenzene, dichlorobenzene, dichloroethane, methyl tert-butyl ether, methyl cyclopentyl ether, isopropyl ether, dibutyl ether, isopropyl acetate, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, and N-butylpyrrolidone; or, the temperature of the esterification reaction is 15℃-35℃, and the time is 3 hours-8 hours.

8. The method for preparing pyranol derivatives or their cis-trans isomers according to claim 7, characterized in that, The molar ratio of the cinnamic acid derivative or its cis-trans isomer to the catalyst is 1:0.03-0.08; and / or the molar ratio of the cinnamic acid derivative or its cis-trans isomer to the condensing agent is 1:1.5-2.

5.

9. The use of the pyranol derivative or its cis-trans isomer as described in any one of claims 1-5 in the preparation of cosmetics or topical skin medications having whitening and / or antioxidant effects.

10. The use of pyranol derivatives or their cis-trans isomers in the preparation of cosmetics or topical skin medications with photoprotective effects, wherein the pyranol derivatives are selected from the following compounds: ； 。 11. A cosmetic or topical skin medication, characterized in that, Its active ingredients include the pyranol derivatives or their cis-trans isomers as described in any one of claims 1-5.

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